BUDESONIDE"

Field of invention:

The present invention relates to an improved process for the preparation of Budesonide on industrial scale. Particularly, the invention relates to improved process for the preparation of Budesonide using Perchloric acid catalyst in water medium.

Background of the invention:

Budesonide is designated chemically as (RS) 16a,17a-(Butylidenedioxy)-l ip,21- dihydroxypregna-l,4-diene-3,20-dione and having a structure of the following Formula-I.

Budesonide is generally known for the treatment of diseases which are associated with inflammation processes. The active ingredient Budesonide has also been used successfully for the treatment of Inflammatory Bowel Disease and Irritable Bowel Syndrome including mild to moderate ulcerative colitis.

Budesonide and other structurally similar glucocorticoids were described for the first time in patent GB 1429922. In this patent, Budesonide is manufactured by reacting 16a-Hydroxy Prednisolone with n-Butyraldehyde in 1, 4-Dioxane in presence of Perchloric acid as a catalyst. This also needs multiple purifications and the crude is purified by column chromatography. Since the 1, 4-Dioxane is used in large quantities; it is projecting to effluent problems and complete recovery of solvent is leading to cost escalation to produce Budesonide. US4835145 and US4695625 discloses a process for the preparation of 16,17-acetals of pregnane derivatives from corresponding 16, 17-acetonides by reaction with aldehydes in aqueous Hydrofluoric acid (HF) and Hydrochloric acid (HC1). US6169178 also discloses a process for the preparation of Budesonide in the presence of aqueous Hydrobromic acid (HBr) and Hydroiodic acid (HI) as reaction catalysts and solvents. However, HI and HF acids are corrosive, light sensitive, expensive and these acids are environmental pollutants.

US5556964 discloses a process for the preparation of Budesonide by reacting 16a- Hydroxy prednisolone in acetonitrile in the presence of p-Toluene sulfonic acid as a catalyst. But this process also involved multiple purification methods increasing time cycle and production cost.

Therefore, there is very much necessity to develop an improved industrially feasible and economically viable process to prepare Budesonide to overcome the problems of the prior art, by reducing the effluents generation and minimizing the use of industrial solvents. The present invention addresses the need by providing cost effective method for the production of Budesonide.

Summary of the invention:

The present inventors have, surprisingly, found a novel process for preparation of Budesonide using Perchloric acid in water medium in good yields and purity. The process of the present invention involves the use of water as medium along with small quantity of an organic solvent as a co-solvent thereby resulting in drastic minimization of formation of impurities, hence, with single purification, Budesonide obtained is conforming to EP-8.0/USP standards. Moreover, this process offers effluent having less COD, minimizes solvent usage and hence decreases recovery of solvent cost, thus improving the time cycle which is ultimately results in increase in productivity.

This newly modified process has great advantage in robust industrial manufacturing process, having high purity and desired epimeric ratio in single purification. The co- solvent may be selected from 1,4-dioxane or Ethyl acetate. Accordingly in one aspect, the present invention provides an industrial process for preparation of Budesonide of the formula-I comprising;

reacting 11 β, 16α, 17α, 21-tetrahydroxypregna-l, 4-diene-3, 20-dione (16a- Hydroxy Prednisolone) of formula-II

with n-Butyraldehyde using Perchloric acid in water medium to obtain Budesonide.

In a preferred embodiment, the present invention provides a process for preparation of Budesonide of the formula-I comprising;

reacting 16a-Hydroxy prednisolone of formula-II in water and 1,4-dioxane or ethyl acetate in the presence of Perchloric acid to obtain Budesonide. Detailed description of the invention:

Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. The term "consists essentially of means excluding other materials that contribute to function.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

Accordingly in one aspect, the present invention provides a process for preparation of Budesonide of the formula-I which comprises reacting 11 β, 16α, 17α, 21- tetrahydroxypregna-1, 4-diene-3, 20-dione (16a-Hydroxy Prednisolone) of Formula-II with n-Butyraldehyde using Perchloric acid in water medium in presence of small volume of co-solvent to obtain Budesonide.

In a preferred embodiment, the present invention provides a process for preparation of Budesonide of the formula-I which comprises reacting 16a-Hydroxy Prednisolone of formula-II with n-Butyraldehyde in water and a small quantity of 1,4-dioxane or ethyl acetate in the presence of Perchloric acid to obtain Budesonide. According to the present invention water as solvent may be used in the range of 2 mL/gm to 10 mL/gm of substrate, 16a-Hydroxy Prednisolone. However, preferably about 5 mL water per gm of 16a-Hydroxy Prednisolone is used.

Along with the water, preferably 1,4-dioxane or ethyl acetate solvent may be used as co solvent during the reaction in very small quantities. Quantity of 1,4-dioxane or ethyl acetate may vary from 0.25 mL to 1.5 mL per gm of 16a-Hydroxy Prednisolone used. However about 0.5 mL of 1,4-dioxane or ethyl acetate per gm of 16a-Hydroxy Prednisolone is preferred.

Usually 16a-Hydroxy Prednisolone of formula-II and n-Butyraldehyde is taken in water and 1,4-dioxane or ethyl acetate is added under an inert atmosphere. To the mixture Perchloric acid is added. Preferably Perchloric acid having 70% strength can be used without dilution with water. Perchloric acid is added to the reaction mixture at about 0°C and maintained the reaction at -5°C to 25°C temperature till completion of reaction. Usually reaction completes in 30 minutes to 150 minutes. After completion of reaction, the product is isolated by conventional procedures such as drowning the mass in water and filtering to isolate the solids. The solids are further dissolved in suitable solvent such as methylene dichloride, washed the solution with water. Optionally, the solution may be treated with charcoal before concentration to isolate crude.

The crude Budesonide is further purified from a mixture of methanol and isopropyl ether solvents to obtain purified Budesonide meeting the specifications of EP and USP in single purification.

The following examples, which include preferred embodiments, are intended to illustrate the practice of this invention. It is being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. EXAMPLES:

EXAMPLE 1

45 ml of water, 5 ml of 1,4-Dioxane, 10 gm of 16a-Hydroxy Prednisolone and 5 ml of n- Butyraldehyde were fed in round bottom flask under nitrogen blanketing. The suspension was cooled to below 0°C. 50 ml Perchloric acid was added within 60 to 120 minutes and completed reaction. Then the reaction mass was poured into 100 ml ice water to obtain suspension.

The suspension was stirred for 30 minutes and filtered the mass. The obtained wet cake was dissolved in methylene dichloride. The aqueous filtrate was extracted twice with methylene dichloride and the extract was combined with methylene dichloride solution. The solution was washed with water till neutral pH.

The methylene dichloride layer was treated with activated carbon for 60 minutes and filtered through celite. The filter cake was washed with methylene dichloride and the filtrate is concentrated under vacuum up to dryness to obtain crude Budesonide in solid form.

Charged 100 mL methanol to the crude Budesonide and heated to reflux till clear solution. Then distilled out methanol under vacuum up to dryness. To the solid mass, added 2.5 mL of methanol and 30 mL of isopropyl ether to obtain the suspension. The reaction mass was refluxed for 60 minutes and cooled to 0-5°C. The suspension was stirred at 0-5°C for 2 hours, filtered the product and washed with chilled Iso Propyl ether. Wet cake was dried in oven.

Dry wt: 10.0 gm

Epimer-A: 42.2%, Epimer-B: 57.7%

Since there is a teaching in EP0875516 about the use of aqueous halo acids (HBr/HI) along with minimum quantity of Tetrahydrofuran (THF), comparative experiments were conducted using 1,4-Dioxane and Ethyl acetate Vs. Tetrahydrofuran under similar conditions as per present invention. And the Quantity Data and Quality Data are tabulated in Table No. 1 and Table No. 2 respectively below.

Table No. l : Quantity details of reactions using 1,4-dioxane & THF & Ethyl acetate :

Table No.2 : Quaiily data of reactions using 1 ,4-dioxane & THF & Ethyl acetate :

Under similar conditions, % of single impurity (0.50%) and % of total impurities (0.78%) in purified Budesonide are higher in THF. Whereas, when 1,4-Dioxane or Ethyl acetate are used the impurities formation is getting reduced.

EXAMPLE 2

112.5 ml of water, 12.5 ml of 1, 4-Dioxane, 25 gm of 16a-Hydroxy Prednisolone and 12.5 ml of n-Butyraldehyde were fed in round bottom flask under nitrogen blanketing. The reaction mixture was cooled to below 0°C. 125 ml of Perchloric acid was added within 60 to 120 minutes and completed reaction. Then the reaction mass was poured into 250 ml ice water, filtered and suck dried to obtain Budesonide (crude).

The wet cake of Budesonide (crude) was dissolved in 125 ml of methylene dichloride. After separation, the main aqueous layer was extracted twice with methylene dichloride and the extract was combined with methylene dichloride solution. The solution was washed with water till neutral pH.

The methylene dichloride layer was treated with activated carbon for 60 minutes and filtered through celite. The filtered cake was washed with methylene dichloride and the filtrate is concentrated under vacuum up to dryness to obtain crude Budesonide in solid form.

Charged 250 mL methanol to the crude Budesonide and heated to reflux till clear solution. Then distilled out methanol under vacuum up to dryness. To the solid mass, added 6.25 mL of methanol and 75 mL of isopropyl ether to obtain suspension. The reaction mass was refluxed for 60 minutes and cooled to 0-5°C. The suspension was stirred at 0-5°C for 2 hours, filtered and washed with chilled isopropyl ether. Wet cake was dried in oven.

Dry wt: 26.0 gm

Epimer-A: 41.9% Epimer-B: 58.0%. EXAMPLE 3

225 ml of water, 25 ml of 1, 4-Dioxane, 50 gm of 16a-Hydroxy Prednisolone and 25 ml of n-Butyraldehyde were fed in round bottom flask under nitrogen blanketing. The reaction mixture was cooled to below 0°C. 250 ml of Perchloric acid was added within 60 to 120 minutes and completed reaction. Then the reaction mass was poured into 500 ml ice water, filtered and suck dried to obtain Budesonide (crude). The wet cake of Budesonide (crude) was dissolved in 250 ml of methylene dichloride. After separation, the main aqueous layer was extracted twice with methylene dichloride and the extract was combined with methylene dichloride solution. The solution was washed with water till neutral pH.

The methylene dichloride layer was treated with activated carbon for 60 minutes and filtered through celite. The filtered cake was washed with methylene dichloride and the filtrate is concentrated under vacuum up to dryness to obtain crude Budesonide in solid form.

Charged 500 mL methanol to the crude Budesonide and heated to reflux till clear solution. Then distilled out methanol under vacuum up to dryness. To the solid mass, added 12.5 mL of methanol and 150 mL of isopropyl ether to obtain suspension. The reaction mass was refluxed for 60 minutes and cooled to 0-5°C. The suspension was stirred at 0-5°C for 2 hours, filtered and washed with chilled isopropyl ether. Wet cake was dried in oven.

Dry wt: 53.0 gm

Epimer-A: 43.02% Epimer-B: 56.9%. EXAMPLE 4

3307.5 ml of water, 367.5 ml of 1, 4-Dioxane, 735 gm of 16a-Hydroxy Prednisolone and 367.5 ml of n-Butyraldehyde were fed in 10 lit round bottom flask under nitrogen blanketing. The reaction mixture was cooled to below 0°C. 3675 ml of Perchloric acid was added within 60 to 120 minutes and completed reaction. Then the reaction mass was poured into 7350 ml ice water, filtered and suck dried to obtain Budesonide (crude).

The wet cake of Budesonide (crude) was dissolved in 3675 ml of methylene dichloride. After separation, the main aqueous layer was extracted twice with methylene dichloride and the extract was combined with methylene dichloride solution. The solution was washed with water till neutral pH.

The methylene dichloride layer was treated with activated carbon for 60 minutes and filtered through celite. The filtered cake was washed with methylene dichloride and the filtrate is concentrated under vacuum up to dryness to obtain crude Budesonide in solid form.

Charged 7350 mL methanol to the crude Budesonide and heated to reflux till clear solution. Then distilled methanol under vacuum up to dryness. To the solid mass, added 183.75 mL of methanol and 2205 mL of isopropyl ether to obtain suspension. The reaction mass was refluxed for 60 minutes and cooled to 0-5°C. The suspension was stirred at 0-5°C for 2 hours, filtered and washed with isopropyl ether. Wet cake was dried in oven.

Dry wt: 773.0 gm

Epimer-A: 42.67% Epimer-B: 57.3%. EXAMPLE 5

45 ml of water, 5 ml of Ethyl acetate, 10 gm of 16a-Hydroxy Prednisolone and 5 ml of n-Butyraldehyde were fed in round bottom flask under nitrogen blanketing. The suspension was cooled to below 0°C. 50 ml Perchloric acid was added within 60 to 120 minutes and completed reaction. Then the reaction mass was poured into 100 ml ice water to obtain suspension.

The suspension was stirred for 30 minutes and filtered the mass. The obtained wet cake was dissolved in methylene dichloride. The main aqueous filtrate was extracted twice with methylene dichloride and the extract was combined with methylene dichloride solution. The solution was washed with water till neutral pH.

The methylene dichloride layer was treated with activated carbon for 60 minutes and filtered through celite. The filter cake was washed with methylene dichloride and the filtrate is concentrated under vacuum up to dryness to obtain crude Budesonide in solid form.

Charged 100 mL methanol to the crude Budesonide and heated to reflux till clear solution. Then distilled out methanol under vacuum up to dryness. To the solid mass, added 2.5 mL of methanol and 30 mL of isopropyl ether to obtain the suspension. The reaction mass was refluxed for 60 minutes and cooled to 0-5°C. The suspension was stirred at 0-5°C for 2 hours, filtered and washed with chilled Iso Propyl ether. Wet cake was dried in oven.

Dry wt: 10.0 gm

Epimer-A: 41.58%, Epimer-B: 58.34%